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WO1992000294A1 - Derive de naphtothiopyranone - Google Patents

Derive de naphtothiopyranone Download PDF

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Publication number
WO1992000294A1
WO1992000294A1 PCT/JP1991/000825 JP9100825W WO9200294A1 WO 1992000294 A1 WO1992000294 A1 WO 1992000294A1 JP 9100825 W JP9100825 W JP 9100825W WO 9200294 A1 WO9200294 A1 WO 9200294A1
Authority
WO
WIPO (PCT)
Prior art keywords
compound
formula
added
action
derivative
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/JP1991/000825
Other languages
English (en)
Japanese (ja)
Inventor
Tatsuhiko Sano
Keiko Saijo
Sadakazu Yokomori
Yoshimoto Nakashima
Katsuo Hatayama
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Taisho Pharmaceutical Co Ltd
Original Assignee
Taisho Pharmaceutical Co Ltd
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Taisho Pharmaceutical Co Ltd filed Critical Taisho Pharmaceutical Co Ltd
Priority to US07/952,544 priority Critical patent/US5347012A/en
Publication of WO1992000294A1 publication Critical patent/WO1992000294A1/fr
Anticipated expiration legal-status Critical
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D249/00—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms
    • C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
    • C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D231/00—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings
    • C07D231/02—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings
    • C07D231/10—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D231/12—Heterocyclic compounds containing 1,2-diazole or hydrogenated 1,2-diazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D233/00—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings
    • C07D233/54—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members
    • C07D233/56—Heterocyclic compounds containing 1,3-diazole or hydrogenated 1,3-diazole rings, not condensed with other rings having two double bonds between ring members or between ring members and non-ring members with only hydrogen atoms or radicals containing only hydrogen and carbon atoms, attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D335/00—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom
    • C07D335/04—Heterocyclic compounds containing six-membered rings having one sulfur atom as the only ring hetero atom condensed with carbocyclic rings or ring systems
    • C07D335/08—Naphthothiopyrans; Hydrogenated naphthothiopyrans
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D409/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms
    • C07D409/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings
    • C07D409/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having sulfur atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms

Definitions

  • the present invention relates to a naphthothiopyranone derivative, and more particularly, to a naphthothiopyranone derivative having a 5-HT [serotonin) antagonistic activity at a 5-HT 3 [serotonin 3] receptor.
  • An object of the present invention is to provide a compound having an antiemetic action based on serotonin 3 receptor antagonism, an intestinal motility control action, an anxiolytic action, and the like, which are more excellent than conventionally known compounds. It is in.
  • the invention relates to the formula
  • R 1 represents a hydrogen atom or an alkyl group having 1 to 4 carbon atoms.
  • a naphthothioviranone derivative represented by or a fe added thereto, and the present invention relates to a compound represented by the formula (I> An intermediate of the compound of the formula
  • the alkyl group having 1 to 4 carbon atoms means a straight or branched one.
  • the acid addition salt of the compound of the formula (I) is a salt to which a pharmacologically acceptable acid is added, such as hydrochloride, hydrobromide, hydroiodide, sulfate, Examples include acetate, citrate, malonate, maleate, tartrate, and succinate.
  • the compound of the formula (I) of the present invention can be produced, for example, by the following method.
  • a compound of the formula (1) is converted into a conventional halogenating agent (eg, hydrobromic acid, thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide) in an organic solvent or without solvent.
  • a conventional halogenating agent eg, hydrobromic acid, thionyl chloride, phosphorus pentachloride, thionyl bromide, phosphorus tribromide
  • halogen atoms include chlorine atoms, bromine atoms and iodine atoms.
  • organic solvents include trihydrazine ⁇ ", o-hatsun, polyester, 'Kunsen, trilenin, chloro-E-holm, di-,'-", carbon tetrachloride, such as it is and the child to use a bi-lysine, to the key " ⁇ chill-phosphate!, a two-to-service re a Mi de ⁇ this'-out ⁇ or, I Li E Ji Ryo A base such as thiophene can also be added.
  • R 1 is as defined above
  • an acid addition salt thereof in an organic solvent in the presence or absence of a base to obtain a compound of the formula (I).
  • triethylamine, viridin, potassium carbonate, sodium carbonate, lithium carbonate, cesium carbonate, sodium hydrogencarbonate, hydrogen hydrogen are used as bases in this reaction.
  • sodium hydroxide, sodium hydroxide, sodium hydroxide, sodium ethoxide, and potassium butoxide can be used (hereinafter, the disclosure of the invention).
  • base is used in the same meaning as used herein.
  • examples of organic solvents include dicopenmetan, chloroform, carbon tetrachloride, tetrachloride.
  • the compound of the formula ⁇ 1> which is an intermediate, is a novel compound and can be produced, for example, by the following method.
  • the compound represented by the formula (E) can be obtained by reacting the compound represented by the formula (II) with lumaldehyde in an organic solvent at room temperature to the boiling point of the solvent in the presence of a base.
  • tetrahydrofuran, dioxane, methanol, ethanol, isopropanol, N, N-dimethylformamide, etc. can be used as the organic solvent.
  • the compound represented by the formula (I) can be obtained by reacting the compound with a base after the compound represented by the formula (I).
  • a base after the compound represented by the formula (I).
  • the organic solvent it is possible to use tetrahydrofuran, dioxane, methanol, ethanol, isobrononol, N, N-dimethylformamide, or the like. it can.
  • the compound of the formula (I) of the present invention is prepared in the form of tablets, granules, capsules, powders, pills, injections, liquids, suppositories and the like, and is orally administered, intramuscularly or intravenously. Can be administered directly or enterally.
  • Each of the above-mentioned preparations contains a conventional excipient (for example, microcrystalline cellulose, starch, Lactose, etc .: using conventional methods such as binders (eg, hydroxypropylcellulose, polyvinylidone, etc.), lubricants (eg, magnesium stearate, talc, etc.) (For example, the method specified in the 12th revised sun pharmacy).
  • the dose of the compound of the formula ( ⁇ ) varies depending on the patient's condition, age, weight, etc., but is usually 0.5 mg to 50 rag for an adult, and is administered once a day. Administer several times a day depending on the symptoms.
  • the solvent was distilled off under reduced pressure, and the residue was purified by silica gel chromatography chromatography (developing solvent; dichloromethane: methanol: ammonia water).
  • Example 3 [(2—methyl-1-imidazolyl) methyl] 111-naphtho [2,1—b] thiovirane-one-one Ol g obtained in Example 3 was converted to methanol. It was dissolved and concentrated hydrochloric acid was added to form a hydrochloride. After evaporating the solvent under reduced pressure, the residue was recrystallized from methanol-lugetil ether to obtain 64 mg of the title compound.
  • Example 4 The compound produced in Example 4 (hereinafter, referred to as compound A :) and the compound described in Example 1 of JP-A-2-209876 (hereinafter, referred to as compound B) were used. Each was suspended in a 0.4% carboxymethylcell ⁇ -ice aqueous solution and used as a test sample.
  • a group of 6 Sungx (body weight: 40-60 g male, 30-50 g female) was used, and a chronic venous force neura was attached 3 days before the P vomiting experiment.
  • the sample prepared above was orally administered to each group at a dose of 0.03 to 313 ⁇ 4, 45 minutes later, cisbratin 301 30 was administered intravenously, and the number of vomiting up to 2 hours later was measured. .
  • the control group to which only the 0.4% carboxymethylcellulose suspension was administered, the number of vomiting up to 2 hours was similarly measured.
  • the compound of the present invention has a serotonin 3 antagonistic action at the serotonin 3 receptor, gastrointestinal dysfunction such as dyspepsia, peptic ulcer, colitis, reflux esophagitis, irritable bowel syndrome, etc. It is effective for the treatment of improvement of various symptoms associated with disability and for the treatment of pain such as migraine and trigeminal neuralgia. He is also impeached for the treatment of nausea and emesis with cancer chemotherapy and radiation therapy, as well as arrhythmia and anxiety.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

Dérivé de naphtothiopyranone de formule générale (I) ou sel d'addition d'acide de ce dérivé. Dans la formule, R1 représente hydrogène ou alkyle C1-C4. Ce composé présente un meilleur effet d'antagonisme vis-à-vis du récepteur de sérotonine 3 que les composés habituels, ainsi que des caractéristiques relatives, à savoir une action antiémétique, une action de régulation des mouvements gastro-intestinaux et une action anxiolytique.
PCT/JP1991/000825 1990-06-22 1991-06-20 Derive de naphtothiopyranone Ceased WO1992000294A1 (fr)

Priority Applications (1)

Application Number Priority Date Filing Date Title
US07/952,544 US5347012A (en) 1990-06-22 1991-06-20 Naphthothiopyranone derivatives

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
JP2/164658 1990-06-22
JP16465890 1990-06-22

Publications (1)

Publication Number Publication Date
WO1992000294A1 true WO1992000294A1 (fr) 1992-01-09

Family

ID=15797351

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/JP1991/000825 Ceased WO1992000294A1 (fr) 1990-06-22 1991-06-20 Derive de naphtothiopyranone

Country Status (5)

Country Link
US (1) US5347012A (fr)
EP (1) EP0535232A4 (fr)
KR (1) KR0167085B1 (fr)
CA (1) CA2086013A1 (fr)
WO (1) WO1992000294A1 (fr)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2186769C2 (ru) * 1996-10-04 2002-08-10 Ново Нордиск А/С N-замещенные азагетероциклические карбоновые кислоты и фармацевтическая композиция
RU2188197C2 (ru) * 1996-10-04 2002-08-27 Ново Нордиск А/С 1,4-дизамещенные пиперазины, способ их получения, фармацевтическая композиция и способ лечения нейрогенного воспаления

Family Cites Families (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
IL91542A0 (en) * 1988-10-06 1990-04-29 Erba Carlo Spa N-imidazolyl-and n-imidazolyl-methyl derivatives of substituted bicyclic compounds,their preparation and pharmaceutical compositions containing them
GB8823980D0 (en) * 1988-10-13 1988-11-23 Glaxo Group Ltd Chemical compounds

Non-Patent Citations (2)

* Cited by examiner, † Cited by third party
Title
CHEMICAL ABSTRACTS, Vol. 93, No. 23, Abstract No. 220537r (Bull. Chem. Soc., Jpn., 53(7), 2046-9). *
CHEMICAL ABSTRACTS, Vol. 94, No. 7, Abstract No. 47079p (J. Org. Chem., 45(23), 4611-15). *

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
RU2186769C2 (ru) * 1996-10-04 2002-08-10 Ново Нордиск А/С N-замещенные азагетероциклические карбоновые кислоты и фармацевтическая композиция
RU2188197C2 (ru) * 1996-10-04 2002-08-27 Ново Нордиск А/С 1,4-дизамещенные пиперазины, способ их получения, фармацевтическая композиция и способ лечения нейрогенного воспаления

Also Published As

Publication number Publication date
EP0535232A4 (en) 1993-05-05
CA2086013A1 (fr) 1991-12-23
EP0535232A1 (fr) 1993-04-07
KR0167085B1 (ko) 1999-01-15
US5347012A (en) 1994-09-13

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